CA1302273C - Pyrimidine derivatives for treatment of rheumatoid arthritis - Google Patents
Pyrimidine derivatives for treatment of rheumatoid arthritisInfo
- Publication number
- CA1302273C CA1302273C CA000558216A CA558216A CA1302273C CA 1302273 C CA1302273 C CA 1302273C CA 000558216 A CA000558216 A CA 000558216A CA 558216 A CA558216 A CA 558216A CA 1302273 C CA1302273 C CA 1302273C
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- Prior art keywords
- rheumatoid arthritis
- pharmaceutically acceptable
- treatment
- dimethoxybenzyl
- diamino
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
ABSTRACT
A compound of formula (I):
A compound of formula (I):
Description
~3~ %73 TREATMENT OF DISEASE
Back~round of the Invention The present invention relates to 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-_]pyrimidine or a pharmaceutically acceptable acid addition salt thereof for treatment of rheumatoid arthritis in a human suffering from rheumatoid arthritis.
UK. Patent No. 1 084 103 (and corresponding U.S. Patent No. 3 322 765) discloses 2,4-diaminopyrido[2,3-_]pyrimidines of the general formula (A):
(A) H2N ~N N J
in which Ra is hydrogen or alkyl and R is inter alia an unsubstituted benzyl group or a benzyl group substituted by one or more halogen atoms, alkyl or alkoxy groups. The compounds of formula (I) were described as having high in vitro and in vivo activity against bacteria or bacterial infections in experimental animals.
Subsequently it has been found that the compounds of formula (A) specifically disclosed in U.K. 1 084 103 show some inhibitory activity against mammalian dihydrofolate reductase (DHFR), and the activity was sufficient to render them potentially useful in the treatment of conditions where inhibition of mammalian DHFR is desirable.
It has further been found that many of these compounds are potent inhibitors of histamine N-methyltransferase (HMT), an enzyme involved in the metabolism of histamine. In this manner they often cause an undesirable accumulation of histamine in organs and tissues. The effects of histamine are well known and any possibility of a further utility for JB/KT/22nd December 1987 ~
~30;~273 these compounds was substantially diminished by their strong inhibition of HMT.
Further investigation showed that a nwnber of other compounds of formula (I) also possessed DHFR inhibitory activity but that these, too, were also potent inhibitors oE HNT. Others, which had acceptably low levels of inhibition of HMT were found to have insufficient activity as inhibitors of DHFR.
European Patent Specification 0021292 and U.S. Patent No. 4372957 disclose that compounds of the formula (B):
~l2 CIH3 N ~ CH2Ar (B) wherein Ar is and R and R are lower (Cl 6) alkyl; and pharmaceutically acceptable acid addition salts thereof are not only very potent inhibitors of mammalian DHFR, but also have acceptably low inhibitory activity against HMT, and are useful in the treatment of proliferative diseases, such as psoriasis, basal and squamous cell carcinomas of the skin, and various forms of cancer including leukemias, lymphomas, sarcomas and solid tumors. Preferably monobasic salts are provided.
JB/KT/22nd December 1987 : . .. ~ - . .
~3~;~273 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]pyrimidine is identified as a preferred compound.
The present invention concerns the use of 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]pyrimidine in the treatment of rheumatoid arthritis.
Thus, in one aspect the present invention is directed to the administration of a compound of formula (I), H2l ~ ~ J~ ~ I ~ ( I) oR2 wherein Rl and R2 are each alkyl of 1 to 4 carbons, or a pharmaceutically acceptable acid addition salt thereof to a human for the treatment of rheumatoid arthritis in a human in need thereof (i.e. a human who has been diagnosed as having the disease rheumatoid arthritis).
In a further aspect the invention provides a compound of formula (I) for use in the treatment of rheumatoid arthritis.
In a yet further aspect the present invention provides a compound of formula (I) for use in the manufacture of a msdicament for ths treatment of rheumatoid arthritis.
Most preferred for use according to the present invention is the compound of formula (I) wherein Rl and R2 are each methyl; this preferred compound is also named 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-_]
pyrimidine.
JB/KT/22nd December 19~7 13~2Z73 The medicinal activity of the compound of formula (I) resides in the free base. The nature of the acid participating in the acid additions salts is of minor importance except in so far as it affects solubility and bioavailability. Such acid addition salts include, for example, those derived from hydrochloric acid, hydriodic acid, sulphuric aicd, phosphoric acid, acetic acid, p-toluenesulphonic acid, methanesulphonic acid, maleic acid, lactic acid, citric aicd, tartartic acid, succinic acid, p-chlorobenzenesulphonic acid, isethionic acid, glucuronic acid, pantothenic acid and lactobionic acid. Preferably the salt is mono-basic salt. The most preferred salt is the isethionate.
As used herein rheumatoid arthritis is defined as a chronic systemic disease of unknown etiology in which symptoms and inflammatory connective-tissue changes predominate in articular and related structures.
Pain, limitation of motion and joint deformity are common. Common synonyms for the term rheumatoid arthritis are atropic arthritis, chronic infectious arthritis and proliferative arthritis. The term treatment of rheumatoid arthritis as used herein also includes treatment of rheumatoid spondylitis, a chronic progressive arthritis affecting the spine and sacroiliac joints, as well as psoriatic athritis by administering a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a human in need thereof.
The compound of formula (I) or its pharmaceutically acceptable acid addition salts may be prepared by any method known in the art for the preparation of compounds of analogous structure, for example as described in the aforementioned European Patent Specification 21292.
Whilst it is possible for the compound of formula (I) and salts thereof to be utilised according to the present invention in the form of the raw chemical, they are preferably presented in the form of a pharmaceutical formulation.
The present invention thus also provides the use of a pharmaceutical formulation comprising as the active ingredient a compound of formula (I) JB/KT/22nd December 1987 or its pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable carrier thereof in the treatment of rheumatoid arthritis in a human.
Methods for the preparation of a pharmaceutical formulation are well known in the art and comprise bringing into association an a~tive compound, i.e.
a compound or salt of formula (I), and a pharmaceutically acceptable carrier therefor.
Pharmaceutical formulations for use in this invention include those suitable for oral, rectal, topical and parenteral administration although of those oral formulations are preferred. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. A
convenient unit dose formulation contains the active compound in amount of from about 1 mg to about 1 g, preferably about 2 mg to about 500 mg, most preferably about 10 mg to 100 mg, to be taken once or several times daily.
All methods for the preparation of such formulations include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules, cachets or tablets each containing a predetermined amount of the active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in inert liquid diluent. Tablets may be optionally coated and, if uncoated, may be optionally scored. Capsules may be prepared by filling the active compound ingredients into the capsule cases and then sealing JB/KT/22nd December 1987 13~22~3 them in the usual manner. Slow or sustained release formulations are also suitable for practice of this invention. Cachets are analogous to capsules wherein the active ingredient together with any accessory ingredient(s) are sealed in a rice paper envelope.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oleaginous vehicles. Such preparations are conveniently presented in unit dosage or multi- dose containers which are sealed after introduction of the formulation until required for use.
Pharmaceutical preparations for topical administration include a compound or salt of formula ~I) together with a suitable vehicle, e.g., preferably one which promotes the passage of the compound or salt through the skin, or a patch containing the compound for application to the skin so that the compound or salt may penetrate the human skin.
It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
JB/KT/22nd December 1987 ~4~ z~
~0 73 As has been described above the compound of the present invention and its salts are useful for the treatment of rheumatoid arthritis. The invention thus provides a method for the treatment of rheumatoid arthritis disease in humans which comprises the administration of an effective amount of a compound of formula (I) or an acid addition salt thereof once or several times a day tu a human having rheumatoid arthritis.
The amount of a compound of formula (I) required for therapeutic effect to treatment rheumatoid arthritis will of course vary with such factors as the severity of the disease, the age and weight of the patient, the route of administration, and where the compound is employed in salt form, the nature of the salt. In general, a suitable dose for the treatment of mammals (including humans) will lie in the range of from about 0.1 to 150 mg per kilogram body weight (mg/kg) per day, preferably in the range from of about 0.3 to about 50 mg/kg, more preferably in the range of about 0.5 to 20 mg/kg in terms of base. For acute treatment of rheumatoid arthritis a suitable regimen may be for example 2 to 5 mg/kg twice a day for 5 days.
For chronic treatment a suitable dose may be for example 0.1 to 0.6 mg/kg one to four times per day for 21 days. All doses (amounts) are in terms of the free base.
Toxic manifestions attributable to active compound are typically those associated with folate depletion, such as bone marrow depression, megaloblastic changes, and gastrointestinal ulceration. Calcium leucovorin (calcium salt of 5-formyl-5,6,7,8-tetrahydrofolic acid) may be administered to effect reversal of these manifestations or to prevent their occurrence.
The administration of calcium leucovorin may be effected concurrently with treatment or at any stage thereof whenever toxic symptoms appear.
Thus, the haematological activity of the active compound can be prevented or reduced by the simultaneous administration of calcium leucovorin.
Consequently, tissue levels of the active compound may be safely raised by increasing the dose of the compound together with a simultaneous administration of leucovorin.
JB/KT/22nd December 1987 ~l3f~22~3 Reference should be had to the Eollowing for background information:
1. British Medical Journal, Vol. 292, p. 431-432 - Treatment of Severe Rhewmatoid Arthritis - 15 February 1986.
2. The Journal of ~heumatology, 12:5, p. 904-905 - Studies of effect of Low dose Methotrexate on Rat Adjuvant Arthritis - 1985.
3. Arthritis and Rheumatism, Vol. 29, No. 7 - Methotrexate Metabolism Analysis in Blood and Liver of Rheumatoid Arthritis Patients - July 1986.
The following Examples, which illustrate the invention, should in no way be construed as constituting a limitation thereof.
Exam~le 1 2.4-Diamino-5-methyl-6-(2.5-dimethoxybenzYl)pYrido~2.3-dl pyrim_dine A mixture of 2,5-dimethoxybenzaldehyde (100 g), ethyl acetoacetate (84.5 g), anhdyrous benzene (200 ml), piperidine (6 ml) and acetic acid (12 ml) was heated at reflux for 3 hours in an apparatus fitted with a Dean-Stark trap to collect the azeotropically distilled water. The reaction mixture was cooled, benzene (300 ml) added, and the solution was washed successively with water (100 ml), cooled 0.1 N hydrochloric acid (200 ml), 5% aqueous sodium bicarbonate (200 ml) and dilute acetic acid (lO0 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure and the residual oil distilled, b.p. 169-170C~0.3 mm Hg.
The product, ethyl _-(2,5-dimethoxybenzylidene)acetoacetate, solidified on standing (104 g, m.p. 68-69C) and was recrystallised from ethanol-pentane (m.p. 72-73C). A portion (38 g) of the product was reduced catalytically in the presence of palladium on charcoal catalyst (Pd/C) in ethyl acetate (150 ml). The product, after removal of solvent, was purified by distillation under reduced pressure to give ethyl ~-(2,5-dimethoxybenzyl)acetoacetate, b.p. 146-148C/0.3 mm Hg.
JB/KT/22nd December 1987 ~3~)2273 g B504 A mixture of ethyl ~-(2,5-dimethoxybenzylacetoacetate (21.2 g) 2,4,6-triaminopyrimidine (10 g) and diphenylether (100 ml) was heated at 190-230 C for 1.5 hours in an apparatus fitted with a Dean-Stark trap and water-ethanol (4 ml) was collected. Methanol (200 ml) and ethanol (50 ml) were added to the cooled reacticn mixture. The resulting solid was collected by filtration and treated with boiling water ~1 l) to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-_]pyrimidine (17 g), m.p. 325-326 C.
2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-_]pyrimidine (8 g) was chlorinated by treatment with Vilsmeier reagent prepared by slowly adding thionyl chloride (28.5 ml) in dry chloroform (25 ml) to a solution of dimethyl formamide (17.5 ml) in chloroform (100 ml) at 0-5C. The cold mixture of the pyridopyrimidine and Vilsmeier reagent was stirred, gradually allowed to reach ambient temperature, and then heated at reflux for 3 hours. It was then treated with ethanolic base (80 ml) maintaining the temperature at 25-30 C with cooling. The brown product formed was isolated, treated further with aqueous ammonia and then recrystallised from ethanol to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-chloropyrido[2,3-_]pyrimidine, m.p. 193-196C (dec.).
The chloro compound (0.3 g) was dissolved in ethanol (200 ml) containing potassium hydroxide (0.2 g). Palladium on charcoal catalyst (0.2 g) was added and hydrogenation commenced. Reduction was complete after 48 hours and yielded 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]
pyrimidine, m.p. 252-254C
Example 2 Injectable Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate qs to 5 mg/ml Propylene glycol 40 ml Ethanol 11 ml Water for Injection 49 ml JB/KT/22nd December 1987 . ' ... ' "' ~ ~ '' '' ~ , .
~3~12~3 Example~3 Iniectable Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxyben~yl)-pyrido[2,3-_]pyrimidine isethionats qs to 5 mg/ml Propylene glycol 40 ml 5% Dextrose solutlon 60 ml Example 4 Tablet Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate 50 mg Lactose 85 mg Potato starch, dried 14.3 mg Magnesium Stearate 0.7 mg Example 5 Capsule Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate 5 mg Lactose 50 mg (in a two part gelatin capsule) JB/KT/22nd December 1987 ~L3~22~3 :`~
Example 6 Preparation of Salt oE Isethionate Acid _ _ _ _ _ Compound of formula tI) wherein R =R =CH3 (488 g) and ethanol (6.0 1) was stirred at 77-78C and isethionic acid (208.1 g in a concentrated aqueous solution con-taining under 6.3 meg. isethionic acid per gram of solution) was added. I'he reaction mixture was continu-ously stirred and cooled to 40C over one hour. The resulting slurry was cooled to 5C for two hours, filtered and washed with ethanol (0.5 1). The crude product was dissolved in hot ethanol-water, treated with charcoal, filtered, and the solution -then chilled -to 5C to crystallise the'product. Yield: 583 grams of 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido~2,3-d]-pyrimidine isethionate, m.p. 220-223C.
Example ?
Activity of 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido(2,3-~)pyrimidlne The compounds were adminis-tered in the ground meal die-t to rats for 14 days beginning on the day of sensitization with Freund's adjuvant according to the procedure described in J. Immunopharmacology, 1 (4), 497 (1979). The severity of the polyarthritis was evaluated on the 16th day after sensitization by a global assessmen-t of the degrees of edema, erythema, scaling and nodules in the joints and tail as described in J. Exp. Med., 121, 185 (1968). The ED50 values tabulated below represent the doses of the arthritic joint score relative to a control group.
Compound ED50 (mg/kg) ';
2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido(2,3-d)pyrimidine isethionate 19 Aspirin 102
Back~round of the Invention The present invention relates to 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-_]pyrimidine or a pharmaceutically acceptable acid addition salt thereof for treatment of rheumatoid arthritis in a human suffering from rheumatoid arthritis.
UK. Patent No. 1 084 103 (and corresponding U.S. Patent No. 3 322 765) discloses 2,4-diaminopyrido[2,3-_]pyrimidines of the general formula (A):
(A) H2N ~N N J
in which Ra is hydrogen or alkyl and R is inter alia an unsubstituted benzyl group or a benzyl group substituted by one or more halogen atoms, alkyl or alkoxy groups. The compounds of formula (I) were described as having high in vitro and in vivo activity against bacteria or bacterial infections in experimental animals.
Subsequently it has been found that the compounds of formula (A) specifically disclosed in U.K. 1 084 103 show some inhibitory activity against mammalian dihydrofolate reductase (DHFR), and the activity was sufficient to render them potentially useful in the treatment of conditions where inhibition of mammalian DHFR is desirable.
It has further been found that many of these compounds are potent inhibitors of histamine N-methyltransferase (HMT), an enzyme involved in the metabolism of histamine. In this manner they often cause an undesirable accumulation of histamine in organs and tissues. The effects of histamine are well known and any possibility of a further utility for JB/KT/22nd December 1987 ~
~30;~273 these compounds was substantially diminished by their strong inhibition of HMT.
Further investigation showed that a nwnber of other compounds of formula (I) also possessed DHFR inhibitory activity but that these, too, were also potent inhibitors oE HNT. Others, which had acceptably low levels of inhibition of HMT were found to have insufficient activity as inhibitors of DHFR.
European Patent Specification 0021292 and U.S. Patent No. 4372957 disclose that compounds of the formula (B):
~l2 CIH3 N ~ CH2Ar (B) wherein Ar is and R and R are lower (Cl 6) alkyl; and pharmaceutically acceptable acid addition salts thereof are not only very potent inhibitors of mammalian DHFR, but also have acceptably low inhibitory activity against HMT, and are useful in the treatment of proliferative diseases, such as psoriasis, basal and squamous cell carcinomas of the skin, and various forms of cancer including leukemias, lymphomas, sarcomas and solid tumors. Preferably monobasic salts are provided.
JB/KT/22nd December 1987 : . .. ~ - . .
~3~;~273 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]pyrimidine is identified as a preferred compound.
The present invention concerns the use of 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]pyrimidine in the treatment of rheumatoid arthritis.
Thus, in one aspect the present invention is directed to the administration of a compound of formula (I), H2l ~ ~ J~ ~ I ~ ( I) oR2 wherein Rl and R2 are each alkyl of 1 to 4 carbons, or a pharmaceutically acceptable acid addition salt thereof to a human for the treatment of rheumatoid arthritis in a human in need thereof (i.e. a human who has been diagnosed as having the disease rheumatoid arthritis).
In a further aspect the invention provides a compound of formula (I) for use in the treatment of rheumatoid arthritis.
In a yet further aspect the present invention provides a compound of formula (I) for use in the manufacture of a msdicament for ths treatment of rheumatoid arthritis.
Most preferred for use according to the present invention is the compound of formula (I) wherein Rl and R2 are each methyl; this preferred compound is also named 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-_]
pyrimidine.
JB/KT/22nd December 19~7 13~2Z73 The medicinal activity of the compound of formula (I) resides in the free base. The nature of the acid participating in the acid additions salts is of minor importance except in so far as it affects solubility and bioavailability. Such acid addition salts include, for example, those derived from hydrochloric acid, hydriodic acid, sulphuric aicd, phosphoric acid, acetic acid, p-toluenesulphonic acid, methanesulphonic acid, maleic acid, lactic acid, citric aicd, tartartic acid, succinic acid, p-chlorobenzenesulphonic acid, isethionic acid, glucuronic acid, pantothenic acid and lactobionic acid. Preferably the salt is mono-basic salt. The most preferred salt is the isethionate.
As used herein rheumatoid arthritis is defined as a chronic systemic disease of unknown etiology in which symptoms and inflammatory connective-tissue changes predominate in articular and related structures.
Pain, limitation of motion and joint deformity are common. Common synonyms for the term rheumatoid arthritis are atropic arthritis, chronic infectious arthritis and proliferative arthritis. The term treatment of rheumatoid arthritis as used herein also includes treatment of rheumatoid spondylitis, a chronic progressive arthritis affecting the spine and sacroiliac joints, as well as psoriatic athritis by administering a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a human in need thereof.
The compound of formula (I) or its pharmaceutically acceptable acid addition salts may be prepared by any method known in the art for the preparation of compounds of analogous structure, for example as described in the aforementioned European Patent Specification 21292.
Whilst it is possible for the compound of formula (I) and salts thereof to be utilised according to the present invention in the form of the raw chemical, they are preferably presented in the form of a pharmaceutical formulation.
The present invention thus also provides the use of a pharmaceutical formulation comprising as the active ingredient a compound of formula (I) JB/KT/22nd December 1987 or its pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable carrier thereof in the treatment of rheumatoid arthritis in a human.
Methods for the preparation of a pharmaceutical formulation are well known in the art and comprise bringing into association an a~tive compound, i.e.
a compound or salt of formula (I), and a pharmaceutically acceptable carrier therefor.
Pharmaceutical formulations for use in this invention include those suitable for oral, rectal, topical and parenteral administration although of those oral formulations are preferred. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. A
convenient unit dose formulation contains the active compound in amount of from about 1 mg to about 1 g, preferably about 2 mg to about 500 mg, most preferably about 10 mg to 100 mg, to be taken once or several times daily.
All methods for the preparation of such formulations include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules, cachets or tablets each containing a predetermined amount of the active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in inert liquid diluent. Tablets may be optionally coated and, if uncoated, may be optionally scored. Capsules may be prepared by filling the active compound ingredients into the capsule cases and then sealing JB/KT/22nd December 1987 13~22~3 them in the usual manner. Slow or sustained release formulations are also suitable for practice of this invention. Cachets are analogous to capsules wherein the active ingredient together with any accessory ingredient(s) are sealed in a rice paper envelope.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oleaginous vehicles. Such preparations are conveniently presented in unit dosage or multi- dose containers which are sealed after introduction of the formulation until required for use.
Pharmaceutical preparations for topical administration include a compound or salt of formula ~I) together with a suitable vehicle, e.g., preferably one which promotes the passage of the compound or salt through the skin, or a patch containing the compound for application to the skin so that the compound or salt may penetrate the human skin.
It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
JB/KT/22nd December 1987 ~4~ z~
~0 73 As has been described above the compound of the present invention and its salts are useful for the treatment of rheumatoid arthritis. The invention thus provides a method for the treatment of rheumatoid arthritis disease in humans which comprises the administration of an effective amount of a compound of formula (I) or an acid addition salt thereof once or several times a day tu a human having rheumatoid arthritis.
The amount of a compound of formula (I) required for therapeutic effect to treatment rheumatoid arthritis will of course vary with such factors as the severity of the disease, the age and weight of the patient, the route of administration, and where the compound is employed in salt form, the nature of the salt. In general, a suitable dose for the treatment of mammals (including humans) will lie in the range of from about 0.1 to 150 mg per kilogram body weight (mg/kg) per day, preferably in the range from of about 0.3 to about 50 mg/kg, more preferably in the range of about 0.5 to 20 mg/kg in terms of base. For acute treatment of rheumatoid arthritis a suitable regimen may be for example 2 to 5 mg/kg twice a day for 5 days.
For chronic treatment a suitable dose may be for example 0.1 to 0.6 mg/kg one to four times per day for 21 days. All doses (amounts) are in terms of the free base.
Toxic manifestions attributable to active compound are typically those associated with folate depletion, such as bone marrow depression, megaloblastic changes, and gastrointestinal ulceration. Calcium leucovorin (calcium salt of 5-formyl-5,6,7,8-tetrahydrofolic acid) may be administered to effect reversal of these manifestations or to prevent their occurrence.
The administration of calcium leucovorin may be effected concurrently with treatment or at any stage thereof whenever toxic symptoms appear.
Thus, the haematological activity of the active compound can be prevented or reduced by the simultaneous administration of calcium leucovorin.
Consequently, tissue levels of the active compound may be safely raised by increasing the dose of the compound together with a simultaneous administration of leucovorin.
JB/KT/22nd December 1987 ~l3f~22~3 Reference should be had to the Eollowing for background information:
1. British Medical Journal, Vol. 292, p. 431-432 - Treatment of Severe Rhewmatoid Arthritis - 15 February 1986.
2. The Journal of ~heumatology, 12:5, p. 904-905 - Studies of effect of Low dose Methotrexate on Rat Adjuvant Arthritis - 1985.
3. Arthritis and Rheumatism, Vol. 29, No. 7 - Methotrexate Metabolism Analysis in Blood and Liver of Rheumatoid Arthritis Patients - July 1986.
The following Examples, which illustrate the invention, should in no way be construed as constituting a limitation thereof.
Exam~le 1 2.4-Diamino-5-methyl-6-(2.5-dimethoxybenzYl)pYrido~2.3-dl pyrim_dine A mixture of 2,5-dimethoxybenzaldehyde (100 g), ethyl acetoacetate (84.5 g), anhdyrous benzene (200 ml), piperidine (6 ml) and acetic acid (12 ml) was heated at reflux for 3 hours in an apparatus fitted with a Dean-Stark trap to collect the azeotropically distilled water. The reaction mixture was cooled, benzene (300 ml) added, and the solution was washed successively with water (100 ml), cooled 0.1 N hydrochloric acid (200 ml), 5% aqueous sodium bicarbonate (200 ml) and dilute acetic acid (lO0 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure and the residual oil distilled, b.p. 169-170C~0.3 mm Hg.
The product, ethyl _-(2,5-dimethoxybenzylidene)acetoacetate, solidified on standing (104 g, m.p. 68-69C) and was recrystallised from ethanol-pentane (m.p. 72-73C). A portion (38 g) of the product was reduced catalytically in the presence of palladium on charcoal catalyst (Pd/C) in ethyl acetate (150 ml). The product, after removal of solvent, was purified by distillation under reduced pressure to give ethyl ~-(2,5-dimethoxybenzyl)acetoacetate, b.p. 146-148C/0.3 mm Hg.
JB/KT/22nd December 1987 ~3~)2273 g B504 A mixture of ethyl ~-(2,5-dimethoxybenzylacetoacetate (21.2 g) 2,4,6-triaminopyrimidine (10 g) and diphenylether (100 ml) was heated at 190-230 C for 1.5 hours in an apparatus fitted with a Dean-Stark trap and water-ethanol (4 ml) was collected. Methanol (200 ml) and ethanol (50 ml) were added to the cooled reacticn mixture. The resulting solid was collected by filtration and treated with boiling water ~1 l) to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-_]pyrimidine (17 g), m.p. 325-326 C.
2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-_]pyrimidine (8 g) was chlorinated by treatment with Vilsmeier reagent prepared by slowly adding thionyl chloride (28.5 ml) in dry chloroform (25 ml) to a solution of dimethyl formamide (17.5 ml) in chloroform (100 ml) at 0-5C. The cold mixture of the pyridopyrimidine and Vilsmeier reagent was stirred, gradually allowed to reach ambient temperature, and then heated at reflux for 3 hours. It was then treated with ethanolic base (80 ml) maintaining the temperature at 25-30 C with cooling. The brown product formed was isolated, treated further with aqueous ammonia and then recrystallised from ethanol to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-chloropyrido[2,3-_]pyrimidine, m.p. 193-196C (dec.).
The chloro compound (0.3 g) was dissolved in ethanol (200 ml) containing potassium hydroxide (0.2 g). Palladium on charcoal catalyst (0.2 g) was added and hydrogenation commenced. Reduction was complete after 48 hours and yielded 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido[2,3-_]
pyrimidine, m.p. 252-254C
Example 2 Injectable Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate qs to 5 mg/ml Propylene glycol 40 ml Ethanol 11 ml Water for Injection 49 ml JB/KT/22nd December 1987 . ' ... ' "' ~ ~ '' '' ~ , .
~3~12~3 Example~3 Iniectable Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxyben~yl)-pyrido[2,3-_]pyrimidine isethionats qs to 5 mg/ml Propylene glycol 40 ml 5% Dextrose solutlon 60 ml Example 4 Tablet Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate 50 mg Lactose 85 mg Potato starch, dried 14.3 mg Magnesium Stearate 0.7 mg Example 5 Capsule Amount 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido[2,3-_]pyrimidine isethionate 5 mg Lactose 50 mg (in a two part gelatin capsule) JB/KT/22nd December 1987 ~L3~22~3 :`~
Example 6 Preparation of Salt oE Isethionate Acid _ _ _ _ _ Compound of formula tI) wherein R =R =CH3 (488 g) and ethanol (6.0 1) was stirred at 77-78C and isethionic acid (208.1 g in a concentrated aqueous solution con-taining under 6.3 meg. isethionic acid per gram of solution) was added. I'he reaction mixture was continu-ously stirred and cooled to 40C over one hour. The resulting slurry was cooled to 5C for two hours, filtered and washed with ethanol (0.5 1). The crude product was dissolved in hot ethanol-water, treated with charcoal, filtered, and the solution -then chilled -to 5C to crystallise the'product. Yield: 583 grams of 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido~2,3-d]-pyrimidine isethionate, m.p. 220-223C.
Example ?
Activity of 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-pyrido(2,3-~)pyrimidlne The compounds were adminis-tered in the ground meal die-t to rats for 14 days beginning on the day of sensitization with Freund's adjuvant according to the procedure described in J. Immunopharmacology, 1 (4), 497 (1979). The severity of the polyarthritis was evaluated on the 16th day after sensitization by a global assessmen-t of the degrees of edema, erythema, scaling and nodules in the joints and tail as described in J. Exp. Med., 121, 185 (1968). The ED50 values tabulated below represent the doses of the arthritic joint score relative to a control group.
Compound ED50 (mg/kg) ';
2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido(2,3-d)pyrimidine isethionate 19 Aspirin 102
Claims (22)
1. Use of a compound of formula (I):
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of rheumatoid arthritis.
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of rheumatoid arthritis.
2. Use of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-pyrimidine or a pharmaceutically acceptable acid addition salt thereof for the manu-facture of a medicament for the treatment of rheumatoid arthritis.
3. Use of the isethionate salt of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine for the manufacture of a medicament for the treatment of rheumatoid arthritis.
4. Use according to claim 1, 2 or 3, wherein the medicament is adapted for oral administration.
5. Use according to claim 1, 2 or 3, wherein the medicament is in the form of a tablet or a capsule.
6. Use of a compound of formula (I):
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof for the treatment of rheumatoid arthritis.
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof for the treatment of rheumatoid arthritis.
7. Use of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[,3-d]pyrimidine or a pharmaceutically acceptable acid addition salt thereof for the treat-ment of rheumatoid arthritis.
8. Use of the isethionate salt of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyridine for the treatment of rheumatoid arthritis.
9. A pharmaceutical composition for the treat-ment of rheumatoid arthritis comprising as active ingredient a compound of formula (I):
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier therefor.
10. A pharmaceutical composition according to claim 9, in a form for oral administration.
11. A pharmaceutical composition according to claim 10, in the form of a tablet or capsule.
12. A pharmaceutical composition according to claim 11, containing said active ingredient in an amount of 10 to 100 mg.
13. A rheumatoid arthritis treating pharma-ceutical composition comprising an amount of a com-pound of formula (I):
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt, pharmacologically acceptable and effective for the treatment of rheumatoid arthritis, in association with a pharmaceutically acceptable carrier.
(I) wherein R1 and R2 are each alkyl of 1 to 4 carbons or a pharmaceutically acceptable acid addition salt, pharmacologically acceptable and effective for the treatment of rheumatoid arthritis, in association with a pharmaceutically acceptable carrier.
14. A composition according to claim 13, in unit dosage form in which said amount is 2 mg to 500 mg.
15. A composition according to claim 14, wherein said form is a tablet or capsule.
16. A rheumatoid arthritis treating pharma-ceutical composition comprising 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[,3-d]pyrimidine or a pharmaceutically acceptable acid addition salt there-of, in an acceptable amount effective for the treat-ment of rheumatoid arthritis, in association with a pharmaceutically acceptable carrier.
17. A rheumatoid arthritis treating pharma-ceutical composition comprising the isethionate salt of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methyl-pyrido[2,3-d]pyrimidine in an acceptable amount effective for the treatment of rheumatoid arthritis, in association with a pharmaceutically acceptable carrier.
18. A composition according to claim 16 or 17, in unit dosage form for oral administration.
19. A composition according to claim 18, in tablet form.
20. A composition according to claim 18, in capsule form.
21. A composition of claim 19 or 20, wherein said amount is 2 mg to 500 mg.
22. A composition of claim 19 or 20, wherein said amount is 10 mg to 100 mg.
#17-01/24/1991
#17-01/24/1991
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878702758A GB8702758D0 (en) | 1987-02-06 | 1987-02-06 | Treatment of disease |
| GB8702758 | 1987-02-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1302273C true CA1302273C (en) | 1992-06-02 |
Family
ID=10611861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000558216A Expired - Fee Related CA1302273C (en) | 1987-02-06 | 1988-02-05 | Pyrimidine derivatives for treatment of rheumatoid arthritis |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4818759A (en) |
| EP (1) | EP0279565B1 (en) |
| JP (1) | JP2527782B2 (en) |
| AT (1) | ATE70977T1 (en) |
| AU (1) | AU606128B2 (en) |
| CA (1) | CA1302273C (en) |
| DE (1) | DE3867251D1 (en) |
| ES (1) | ES2039610T3 (en) |
| GB (1) | GB8702758D0 (en) |
| GR (1) | GR3003880T3 (en) |
| ZA (1) | ZA88830B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1229203B (en) * | 1989-03-22 | 1991-07-25 | Bioresearch Spa | USE OF 5 METHYLTHETRAHYDROPHOLIC ACID, 5 FORMYLTHETRAHYDROPHOLIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE ACTIVE IN THE THERAPY OF MENTAL AND ORGANIC DISORDERS. |
| PT100905A (en) * | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| ATE305303T1 (en) * | 2001-02-12 | 2005-10-15 | Hoffmann La Roche | 6-SUBSTITUTED PYRIDOPYRIMIDINES |
| EP1896035B1 (en) | 2004-06-16 | 2014-10-15 | Jack L. Arbiser | Carbazole formulations for the treatment of psoriasis and angiogenesis |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3322765A (en) * | 1963-10-30 | 1967-05-30 | Burroughs Wellcome Co | 2, 4-diamino-6-benzylpyrido-(2, 3-d) pyrimidines and method |
| JPS5618982A (en) * | 1979-06-14 | 1981-02-23 | Wellcome Found | Pyrimidine derivatives and medicinal drug containing them |
| DE3062268D1 (en) * | 1979-06-14 | 1983-04-14 | Wellcome Found | Alkoxybenzylpyridopyrimidines, methods for their preparation and pharmaceutical formulations thereof |
| ZA861235B (en) * | 1985-03-08 | 1986-10-29 | Univ Princeton | Pyrido(2,3-d)pyrimidine derivatives |
| EP0278686A1 (en) * | 1987-02-07 | 1988-08-17 | The Wellcome Foundation Limited | Pyridopyrimidines methods for their preparation and pharmaceutical formulations thereof |
| SE9801992D0 (en) * | 1998-06-04 | 1998-06-04 | Astra Ab | New 3-aryl-2-hydroxypropionic acid derivative I |
-
1987
- 1987-02-06 GB GB878702758A patent/GB8702758D0/en active Pending
-
1988
- 1988-02-05 AT AT88300959T patent/ATE70977T1/en not_active IP Right Cessation
- 1988-02-05 CA CA000558216A patent/CA1302273C/en not_active Expired - Fee Related
- 1988-02-05 EP EP88300959A patent/EP0279565B1/en not_active Expired - Lifetime
- 1988-02-05 JP JP63025564A patent/JP2527782B2/en not_active Expired - Fee Related
- 1988-02-05 ES ES198888300959T patent/ES2039610T3/en not_active Expired - Lifetime
- 1988-02-05 DE DE8888300959T patent/DE3867251D1/en not_active Expired - Fee Related
- 1988-02-05 AU AU11357/88A patent/AU606128B2/en not_active Ceased
- 1988-02-05 ZA ZA88830A patent/ZA88830B/en unknown
- 1988-02-05 US US07/152,837 patent/US4818759A/en not_active Expired - Lifetime
-
1992
- 1992-02-25 GR GR920400302T patent/GR3003880T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1135788A (en) | 1988-08-11 |
| JPS63216884A (en) | 1988-09-09 |
| GR3003880T3 (en) | 1993-03-16 |
| ZA88830B (en) | 1989-10-25 |
| AU606128B2 (en) | 1991-01-31 |
| ATE70977T1 (en) | 1992-01-15 |
| GB8702758D0 (en) | 1987-03-11 |
| US4818759A (en) | 1989-04-04 |
| JP2527782B2 (en) | 1996-08-28 |
| EP0279565A1 (en) | 1988-08-24 |
| EP0279565B1 (en) | 1992-01-02 |
| ES2039610T3 (en) | 1993-10-01 |
| DE3867251D1 (en) | 1992-02-13 |
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